tbuckley/cabot-search huggingface dataset:
Abstract 11622: A Case of Successful Malignant Lymphoma Treatment Following Transcatheter Aortic Valve Replacement
Authors: Takumi Osawa, Kazuko Tajiri, Masaki Ieda
Journal: Circulation (2022)

Doxorubicin, an anthracycline drug, is a key drug in the treatment for diffuse large B-cell lymphoma (DLBCL). It is contraindicated in patients with serious heart diseases due to the cardiotoxicity. Transcatheter aortic valve replacement (TAVR) has been an established treatment for patients with severe aortic stenosis (AS) at high or prohibitive risk for surgical aortic valve replacement (SAVR). A 67-year-old woman was referred to our department with severe AS. Two months ago, the patient presented with bilateral cervical and inguinal lymphadenopathy. A biopsy of the lymph nodes revealed the primary diffuse large B-cell lymphoma (DLBCL). The patient had been diagnosed with stage IVA non-Hodgkin lymphoma according to the Ann Arbor staging system. The echocardiogram demonstrated a left ventricular ejection fraction of 67% and severe bicuspid AS with a peak velocity of 4.1 m/sec, mean pressure gradient of 44.1 mmHg, and aortic valve area of 0.58 cm 2 . She was initially treated with chemotherapy without anthracycline due to the high risk of anthracycline cardiotoxicity. However, anthracyclines were thought to be essential for controlling DLBCL. She was referred to our department and evaluated from the heart-team, which considered the following characteristics: severe impairment of mobility and frailty with a Society of Thoracic Surgeons (STS) score of 5.99%. Due to the high surgical risk for SAVR, we decided to perform TAVR. The procedure was completed without complications during the perioperative period. Ten days after TAVR, the patient received the therapy of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), which resulted in complete remission without cardiac symptoms. Before the advent of TAVR, it was difficult for patients with both severe AS and cancer to receive surgery and/or cardiotoxic treatment. In patients with cancer, AS may interfere with optimal antineoplastic therapy (ie, high-risk oncological surgery and/or cardiotoxic anticancer drugs). TAVR does not need cardiac arrest, extracorporeal circulation, and thoracotomy. TAVR could increase therapeutic options in cancer patients with severe AS who are at high surgical risk.
Abstract 12437: Characteristics and Prognostic Impact of Concomitant Tricuspid Regurgitation in Patients With Severe Aortic Stenosis Undergoing Transcatheter Aortic Valve Implantation
Authors: Takumi Osawa, Kimi Sato, Naoto Kawamatsu, Masayoshi Yamamoto, Tomoko Machino, Tomoya Hoshi, Tomoko Ishizu, Masaki Ieda
Journal: Circulation (2022)

Introductions: Previous studies have shown that concomitant presence of tricuspid regurgitation (TR) was associated with poor prognosis in patients with severe aortic stenosis (AS) who underwent transcatheter aortic valve implantation (TAVI). Nonetheless, another report suggested that impact of TR was affected by mitral regurgitation (MR) severity. We aim to investigate the imaging characteristics of concomitant TR according to the MR severity and its prognostic impact in patients who underwent TAVI. Methods: We studied 129 patients with severe AS who underwent TAVI from 2015 to 2020 (mean age 84 years; male 33%). We subdivided patients according to the presence of TR and MR (≥ moderate) and compared the imaging characteristics and prognosis. Results: Significant TR was observed in 25 patients (19%); among those with TR, 15 had both MR and TR and remaining 10 had only TR (Figure A). Patients with TR showed impaired right ventricular (RV) systolic function and higher tricuspid annulus area and RV end-diastolic volume (p &lt; 0.05 for all). When we further compare the characteristics of patients with TR according to the MR severity, RV systolic function, tricuspid annulus area, or RV volume were similar regardless of the MR severity, while left ventricular (LV) volume was significantly smaller in patients with significant TR alone. During the follow-up, 15 patients experienced all-cause death. Patients with TR alone showed poorer all-cause mortality (Log-rank p = 0.008; Figure B). In multivariable Cox proportional-hazards model, TR was independently associated with all-cause mortality in the absence of MR (hazard ratio 4.94, p = 0.008). Conclusions: In patients undergoing TAVI, significant TR was associated with advanced RV remodeling regardless of MR status, while patients who only exhibited TR had less LV remodeling. Concomitant TR was associated with poorer outcome in the absence of MR, indicating that could be an independent risk factor in patients undergoing TAVI.
Abstract 11274: VERVE-101—An Investigational Single-Course Gene Editing Medicine Targeting PCSK9—Durably and Potently Lowers PCSK9 and LDL-C Concentrations in Non-Human Primates
Authors: Richard Lee, Anne M Mazzola, Maurine Braun, Colin Platt, Scott Vafai, Sekar Kathiresan, ellen rohde, Andrew M Bellinger, Amit V Khera
Journal: Circulation (2022)

Introduction: VERVE-101 is an in vivo CRISPR base editing therapy designed to alter a single DNA base in the PCSK9 gene, permanently inactivate hepatic expression, and thereby durably lower LDL cholesterol (LDL-C). Here, we test the efficacy, tolerability, and potential for germline editing of VERVE-101 in studies of 43 non-human primates. Methods: Cynomolgus monkeys were dosed with a single intravenous infusion of a vehicle control (N = 10) or VERVE-101 at a dose of 0.75 mg/kg (N = 4) or 1.5 mg/kg (N = 22) with subsequent assessment of liver PCSK9 editing, reductions in blood PCSK9 and LDL-C, and safety parameters. A second study evaluated sexually mature male non-human primates dosed with a vehicle control (N = 1) or 1.5 mg/kg of VERVE-101 (N=6) to assess for any germline cell editing. Results: Liver biopsies 14 days after dosing noted mean PCSK9 editing of 46% and 70% in monkeys treated with VERVE-101 at 0.75 and 1.5 mg/kg respectively. This translated into reductions in blood PCSK9 of 69% and 89% and reductions of LDL-C of 50% and 68% at the 0.75 and 1.5 mg/kg doses, respectively, measured one year after dosing ( Figure). Liver safety monitoring noted a transient rise in ALT and AST concentrations following infusion that fully resolved by day 14 with no accompanying change in total bilirubin. VERVE-101 did not impact glucose homeostasis, as assessed by serial monitoring of fasting glucose and hemoglobin A1c. In the study to assess germline editing, VERVE-101 was similarly well tolerated and no editing of PCSK9 was observed in sperm samples obtained 90 days after dosing. Conclusions: A single intravenous infusion of VERVE-101 in non-human primates was well-tolerated and led to 89% lower blood PCSK9 protein and 68% lower blood LDL-C at one year after dosing. These results support initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease, with initial patient dosing anticipated in mid-2022.
Abstract 11471: Engineered Bacterial Sodium Channel Gene Therapy Prevents Contractile Deficit and Reduces Ventricular Arrhythmias in a Non-Human Primate Model of Myocardial Infarction
Authors: Tianyu Wu, Sze-Jie Loo, Yu Gao, Jun-Hua Luo, liping Su, Nicole Gee-Zhi Tee, Lei Ye, Nenad Bursac
Journal: Circulation (2022)

Introduction: Current therapies for myocardial infarction (MI) and sudden cardiac death are limited. The ability to enhance amplitudes of sodium current and calcium transient in cardiomyocytes could improve electrical synchrony and contractions of infarcted heart tissue to both prevent arrhythmias and improve pumping function. We hypothesized that adeno-associated virus (AAV) delivery of prokaryotic sodium channel (BacNa v ) can improve electrical and contractile function of infarcted hearts. Methods: MI in non-human primates (NHPs) was induced by 60-min ischemia / reperfusion injury. Animals were randomized to sham surgery (n=6) or MI followed by intramyocardial injection of AAV-BacNa v (n=6) or AAV-GFP (n=6) into the infarct area and border zone. Left ventricular (LV) function was assessed by echocardiogram at baseline, 1- and 4-week post-MI. Spontaneous arrhythmias were tracked by a subcutaneously implanted loop recorder during the 4-week study period. Results: At 4 weeks post-MI, BacNa v and GFP expression were detected in all treated animals (Fig. 1). Compared to sham animals, GFP-treated animals showed lower LV ejection fraction (LVEF, 37.4±3.4% vs 58.2±1.2%, p&lt;0.0001) and increased LV end-systolic volume (3.8±0.57mL vs 2.1±0.25mL, p&lt;0.05). BacNa v -treated animals showed significant increase in LVEF compared to the GFP group (48.3±3.4% vs 37.4±3.4%, p&lt;0.05) and did not differ from the sham group. Compared to the GFP group, fewer BacNa v -treated animals displayed spontaneous arrhythmias (16.7% vs 100%, p&lt;0.05) and had less arrhythmia episodes per animal (0.17±0.17 vs 2.17±0.6, p&lt;0.01), while not differing in any measured electrophysiological parameters from the sham group. Conclusion: The AAV-mediated BacNa v expression in cardiomyocytes can alleviate cardiac contractile deficit and reduce ventricular arrhythmias in the setting of MI in an NHP model. BacNa v gene delivery may represent a promising therapeutic strategy for the treatment of MI.
Abstract 12305: Cardiac Computed Tomography Derived Aorta and Aortic Arch Z-scores in Children
Authors: Rakesh Donthula, Harmanpreet Kaur, Wen Li, santosh uppu
Journal: Circulation (2022)

Introduction: Echocardiogram, Cardiac Magnetic Resonance Imaging, and Computed Tomography Angiography (CTA) play a key role in the diagnosis and follow-up of congenital heart disease patients. Our objective was to establish CTA-derived normative data for aortic root (AoR), aortic sinotubular junction (STJ), ascending aorta (AAO), proximal (PAA), distal transverse aortic arch (DAA), isthmus (Is), and descending aorta (DAO) in children. Methods: Maximum, minimum, and mean diameters for STJ, AAO, PAA, DAA, Is, and DAO in systole and diastole were measured in 100 subjects who had CTA between January 2015 through December 2020 with no intracardiac defect or shunt lesion. The allometric exponent (AE) for each parameter was derived, and the parameter/body surface area (BSA)^AE is established using previously described methods. Regression analysis is performed to demonstrate a linear relationship to BSA. Using this data, normalized mean and standard deviation (SD) are calculated for all the structures mentioned and z-score curves are plotted in relation to BSA. Results: The normalized mean diameters (mm) in systole for AoR is 19.67 ± 1.99, STJ 17.25 ± 1.77, AAO 17.73 ± 2.18, PAA 16.39 ± 2.05, DAA 15.32 ± 1.75, Is 14.25 ± 1.69, and DAO 12.46 ± 1.64. For diastole, AoR is 18.87 ± 1.83, STJ 16.39 ± 1.77, AAO 16.39 ± 2.07, PAA 15.04 ± 2.13, DAA 14.22 ± 1.78, Is 13.26 ± 1.58, and DAO 11.66 ± 1.33. The figure shows the z-score plots. Conclusions: This is the first study in children that provides normative CTA-derived data for the AoR, STJ, AAO, PAA, DAA, Is, and DAO. This data is helpful to guide medical and surgical decision-making in children with congenital heart disease.
Abstract 11334: Validation of Deep-Learning-Based Retinal Biomarker in the Prediction of Cardiovascular Disease: Data From AREDS
Authors: Hyun Goo Kang, Tyler Hyungtaek Rim, Qingyu Chen, Zhiyong Lu, Chan Joo Lee, Yih-Chung Tham, Sahil Thakur, Simon Nusinovici, Qingsheng Peng, Marco Yu, Geunyoung Lee, Sung Ha Park, Sung Soo Kim, Tiarnan Keenan, Tien Y Wong, Emily Chew, Ching-Yu Cheng
Journal: Circulation (2022)

Background: In our previous study, we developed a deep-learning-based novel cardiovascular disease (CVD) risk stratification system based on retinal photographs, Reti-CVD. This study aims to further validate Reti-CVD in the US population of the Age-Related Eye Disease Studies (AREDS). Methods: Our testing cohort comprises of AREDS participants who have undergone retinal photography. We evaluated the ability of Reti-CVD to predict atherosclerotic CVD (ASCVD) events (non-fatal and fatal events, and fatal events) using Cox proportional-hazards models. Reti-CVD scores were then calculated and stratified into three groups based on optimized cut-off values from AREDS. Upon further stratifying Reti-CVD scores, we evaluated whether adding Reti-CVD to traditional risk factors could improve risk prediction. Results: Among 3,555 participants, 282 (7.9%) had non-fatal and fatal ASCVD events, and 84 (2.4%) had fatal ASCVD during the 13-year follow-up. Reti-CVD was significantly associated with an increased risk of ASCVD, demonstrating an adjusted hazard ratio (HR) trend of 1.13 (95% CI, 1.03-1.24) for non-fatal and fatal ASCVD events, and an adjusted HR trend of 1.27 (1.07-1.52) for fatal ASCVD events. Reti-CVD significantly improved the overall predictive performance of traditional risk models with a continuous net reclassification index (NRI) of 0.247 (0.106-0.364) for non-fatal and fatal ASCVD events, and 0.232 (0.107-0.359) for fatal ASCVD events. In heatmaps, traditional risk features such as arteriovenous nicking and arteriolar narrowing were well-detected by the Reti-CVD algorithm. Conclusions: A deep-learning-based, retinal photograph-derived new CVD biomarker, Reti-CVD, can be utilized as a risk stratification tool in predicting ASCVD risk in the US population. With the improvements observed on the current risk stratification by traditional risk models, Reti-CVD has considerable potential as an enhanced CVD risk stratification tool applicable in the general US population.
Abstract 12402: Sacubitril-Valsartan Increases Pampk and Reduces Inflammasome, Myddosome, Il-6 and Galectin-3 Levels in Short-Term Doxorubicin-Treated Mice Improving Longitudinal Strain and Ejection Fraction
Authors: Nicola Maurea, Maria Laura Canale, Simona Buccolo, Irma Bisceglia, Andrea Paccone, Fabrizio Maurea, Marino Scherillo, Vincenzo Quagliariello
Journal: Circulation (2022)

Introduction: Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril-valsartan (LCZ 696) is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, used for the treatment of heart failure in patients with a reduced ejection fraction. Hypothesis: We hypothesized that LCZ 696, administered during doxorubicin, could improve cardiac function Methods: Female C57Bl/6 mice were untreated (Sham, n=6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n=6), LCZ-696 at 60 mg/kg (LCZ, n=6) or doxorubicin combined to LCZ-696 (DOXO-LCZ, n=6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, DAMPs (galectine 3 and calgranulinS100) , pAMPK, NF-kB, and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified through ELISA and western blot methods. Results: LCZ 696 improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88, DAMPs and NF-kB in cardiac tissues was seen in DOXO-LCZ group compared to DOXO mice (p&lt;0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with LCZ-696 indicating anti-inflammatory properties. Expression of pAMPK was strongly enhanced in LCZ-696-DOXO compared to DOXO group. Levels of Calgranulin S100 and galectine-3 were strongly enhanced in DOXO group; on the other hand their expression were reduced by 47.7 and 52.3% in LCZ-696-DOXO group vs DOXO (p&lt;0.005). Conclusions: LCZ-696 is able to improve cardiac function and reduce biomarkers involved in heart failure and fibrosis. The overall picture of the study pushes the use of Sacubitril-valsartan in prevention of cardiomyopathies induced by anthracyclines in cancer patients.
Abstract 11779: Impinged RCA: Who's the Culprit?
Authors: Pooja Mishra, Muhammad Ahmad, Izza Saeed, Joaquin Gonzalez
Journal: Circulation (2022)

Introduction: Post-sternotomy chest pain (CP) has been widely reported in literature. The etiologies include myocardial infarction, pulmonary embolism, hypersensitivity reactions to foreign material, wound infection, sternal instability and dehiscence, neuropathic pain due to intercoastal nerve damage or sternal wire fracture leading to migration. Here, we report a rare case of a young patient who presented with chronic chest pain after an atrial septal defect (ASD) repair. Case: A 28-year-old male with past medical history significant for an ASD (secundum) repair with autologous pericardial patch, hyperlipidemia, COVID-19 infection, known first degree AV block, and early repolarization changes, presented for a follow-up office visit three years after his ASD repair with complaints of typical anginal symptoms. Diagnosis: Vitals, physical exam, troponin, D-dimer and inflammatory markers were unremarkable. Chest x-ray (Figure 1A) showed sternal wires in place and no fractures of wires. EKG (Figure 1B) was unchanged. Echocardiogram showed LVEF 50% and no wall motion abnormalities. He underwent a coronary CTA which identified intermittent compression on the mid-RCA from the third bottom stainless steel sternal wire (Figure 1C), warranting removal. Treatment: He underwent explantation of all sternal wires and selective right coronary angiography (Figure 1D) was performed, which revealed intact and patent RCA without any complications. He continues to follow-up in our clinic without any CP. Conclusions: Chronic CP after any cardiac surgery remains a diagnostic dilemma and a source of anxiety for patients. We recommend comprehensive discussions with patients prior to surgery about these probable complications to alleviate the anxiety. Lastly, from research thus far, removal of sternal wires is a safe, simple, and effective procedure that should be offered to patients with persistent post-sternotomy CP after exclusion of serious complications.
Abstract 11795: Sex Modifies Compositional Plaque Progression in Non-Obstructive Coronary Artery Disease
Authors: Caroline A Berge, Margrete Solvik, Ingela Khan, Eva R Pedersen, Terje Hjalmar Larsen, Siren Hovland, Mai Tone Lonnebakken
Journal: Circulation (2022)

Introduction: Coronary artery disease (CAD) is a progressive disease where plaque composition is associated with cardiovascular events. Whether sex modifies compositional plaque progression in non-obstructive CAD is less explored. Methods: We identified 34 patients with non-obstructive CAD (&lt;50% stenosis) undergoing clinically indicated serial coronary computed tomography angiography (CCTA) with &gt;1 year interscan interval from the Norwegian Registry of Invasive Cardiology. All coronary segments were analyzed at baseline and follow-up using a semi-automated analysis software. We assessed the annual progression rate in total and compositional plaque volumes among women and men. Results: In the total study population (mean age 59.9 ± 11.3 years, median interscan interval 1.9 years [interquartile range (IQR): 1.6-2.3 years]), 41% were women. Women were older (64.9 ± 8.0 years vs. 56.3 ± 12.0 years, p=0.025), while there was no significant difference in the prevalence of hypertension, diabetes, statin treatment or smoking between groups (all p&gt;0.05). Women had a higher total plaque burden at baseline and follow-up compared to men (p=0.017 and p=0.026, respectively), and their plaque composition remained unaltered (Figure 1). To the contrary, men had a higher progression rate of hypodense plaque proportions, comprising necrotic core (-30 - 30 HU) and fibrous fatty (31 - 130 HU) plaque (p=0.046 and p=0.019, respectively), with an associated increase in diseased segments at follow-up (p=0.003). Conclusions: In non-obstructive CAD, women had a higher plaque burden and an unaltered plaque composition, while men had faster progression of hypodense plaque proportions in serial CCTA. Whether sex differences in compositional plaque progression is associated with prognosis in non-obstructive CAD needs further investigation.
Abstract 11969: Effect of Aortic Valve Phenotype and Sex on Aortic Dilation: Results From the Progressa Study
Authors: Marie-Ange Fleury, Lionel Tastet, Mylene Shen, Romain Capoulade, Jeremy Bernard, Kathia Abdoun, Elisabeth Bédard, Marie Arsenault, Marie-Annick Clavel, Philippe Pibarot
Journal: Circulation (2022)

Introduction: Bicuspid aortic valve (BAV) is frequently associated with aortic valve stenosis (AS) and concomitant aortopathy. However, few studies have evaluated the effect of aortic valve (AV) phenotype on the risk of progressive dilation of aorta dimensions. The aim of this study was to compare the progression rate of aorta dimensions according to AV phenotype (i.e. BAV vs tricuspid aortic valve [TAV]) and sex in patients with AS. Methods: Three-hundred twenty AS patients (231 TAV and 89 BAV; mean age: 64±14 years, 72% men) recruited in the PROGRESSA study (NCT01679431) were included in this analysis. Patients underwent Doppler-echocardiography annually to measure the AS hemodynamic severity and aorta dimensions including the aortic root (AR) at the sinus level and ascending aorta (AA) sections. The annualized change of echocardiographic parameters was assessed between baseline and last follow-up visit (median follow-up time: 4.01 [2.26 to 5.00] years). Results: Baseline AR diameters were similar between phenotypes and AA diameters were larger in BAV vs. TAV (34±5 vs. 34±4, p=0.43, 38±6 vs. 34±4, p&lt;0.001, respectively). Median change in AR root diameter was similar in BAV vs. TAV (0.15 [-0.07 to 0.44] cm/year vs. 0.13 [-0.07 to 0.41] cm/year, p=0.69), whereas AA annualized change was larger in BAV (0.26 [0.02 to 0.52] cm/year vs. 0.14 [-0.06 to 0.40] cm/year, p=0.02). After multivariable adjustment, BAV phenotype was not a significant predictor of faster progression rate of AR or AA dilation (β: -0.003, p=0.98 and -0.095, p=0.25). In a separate analysis according to sex, the median changes in AR and AA were similar between women and men (p=0.53 and p=0.18). Predictors of AA progression rate in men were baseline AA diameter and AS severity (i.e. baseline peak aortic jet velocity) (all p≤0.03). In women, only higher low-density lipoprotein levels were significantly associated with faster AA progression (p=0.02). Regarding the AR annualized dilation, there were no significant predictors in both women and men (all p≥0.07). Conclusion: This study suggests that AV phenotype is not independently associated with faster dilation of the AR or AA in patients with established AS. However, the determinants of aorta dilation may be different between women and men.